Na_V channel α-subunit domains and β-subunits. (A) Key structural features of the Na_V channel α-subunit. The four internally homologous domains, DI–IV, are color-coded and labeled. Within DI, the transmembrane helices, S1–6 (including the positively-charged S4 helix), the voltage-sensing domain (VSD), and the S5–6 extracellular turret loop (ECTL) are labeled. (B) Cryo-EM structure of human Na_V1.5 in top and side view (PDB: 7DTC). (C) The resolved binding sites of β1 (magenta), β2 (cyan), and β4 (yellow) based on cryo-EM structures of human Na_V1.1 (PDB: 7DTD); Na_V1.2 (PDB: 6J8E) and Na_V1.4 (PDB: 6AGF), as depicted from top and side views.